CN114456101A - Synthesis method of key intermediate for synthesizing PF-07321332 - Google Patents

Synthesis method of key intermediate for synthesizing PF-07321332 Download PDF

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CN114456101A
CN114456101A CN202111593448.5A CN202111593448A CN114456101A CN 114456101 A CN114456101 A CN 114456101A CN 202111593448 A CN202111593448 A CN 202111593448A CN 114456101 A CN114456101 A CN 114456101A
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dimethyl
azabicyclo
hexane
zinc
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杨凯
赵培新
张庆民
张健
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Shanghai Can Yi Biotechnology Co ltd
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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Abstract

The invention relates to a synthesis method of a key intermediate for synthesizing PF-07321332, wherein the key intermediate specifically comprises N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salts thereof, and belongs to the technical field of organic synthesis, and the synthesis method comprises the following steps: a compound I (the structural formula of the compound I is shown in the specification) and 2, 2-dihalopropane are subjected to Simmons-Smith cyclopropanation reaction to obtain a compound II, namely a synthetic method of N-protected methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic ester; the invention directly constructs a three-membered ring key intermediate by using a cheap and easily obtained double bond substrate compound I and an easily obtained gem-dihalopropane through Simmons-Smith cyclopropanation. Compared with the prior synthesis method, the method shortens the synthesis which needs about 8 steps to 3 steps, obviously reduces the synthesis cost and is more environment-friendly.

Description

Synthesis method of key intermediate for synthesizing PF-07321332
Technical Field
The invention belongs to the technical field of organic synthesis, in particular to a synthesis method of a key intermediate for synthesizing PF-07321332, the key intermediates specifically include N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salts thereof, namely, the invention relates to a method for synthesizing N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate, and a method for synthesizing (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salts thereof.
Background
The compound IV (see below) and the protecting group derivatives are key intermediates for synthesizing Hepatitis C (HCV) therapeutic drugs, namely the Boceprevir (see below) and 2019 coronavirus (COVID-19) therapeutic drug PF-07321332 (see below).
PF-07321332 is an oral compound developed autonomously by pfizer to inhibit the replication of new coronaviruses in humans. In vitro experiments prove that PF-07321332 can specifically inhibit 3CL endoprotease, thereby inhibiting virus replication in human body. The oral medicament Paxlovid can effectively reduce severe and death events for new coronary patients with mild and moderate symptoms but without hospitalization, and the protection efficiency reaches 89%.
Figure BDA0003429899590000011
The current synthetic route for compound IV is as follows (WO 2012/049688A l): the synthesis route is long and uses virulent reagents such as potassium cyanide, and the compound with the required configuration needs to be resolved, so that a large amount of materials are consumed.
Figure BDA0003429899590000021
The starting material is caronic anhydride, which is generally obtained by oxidizing and ring closing the chrysanthemic acid ester compounds, and the caronic anhydride is difficult to obtain and has high cost and more dangerous wastes.
Figure BDA0003429899590000022
Disclosure of Invention
The object of the present invention is to overcome the above technical drawbacks and to provide a synthesis process for the synthesis of key intermediates of PF-07321332, including in particular N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salts thereof. The invention provides a synthetic method of N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate, and simultaneously provides a synthetic method of (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salt thereof, and a three-membered ring key intermediate is directly constructed by using cheap and easily-obtained double bond substrate compound I and easily-obtained geminal dihalogenopropane through Simmons-Smith cyclopropanation. Compared with the prior synthesis method, the method shortens the synthesis which needs about 8 steps to 3 steps, obviously reduces the synthesis cost and is more environment-friendly.
The specific technical scheme of the invention is as follows:
a method for synthesizing N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate, which is characterized by comprising the following steps:
the synthesis method comprises the following steps of carrying out Simmons-Smith cyclopropanation reaction on a compound I (the structural formula of the compound I is shown in the specification) and 2, 2-dihalopropane to obtain a compound II, namely a synthetic method of N-protected methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic ester; the compound I is prepared by adopting a method in the prior art, can be prepared by utilizing starting raw materials with wide sources and low price, and can also be a commercially available compound I. Are not described in detail herein, nor are they intended to be limiting.
The synthetic route is as follows:
Figure BDA0003429899590000031
wherein PG is a protecting group, and PG is a protecting group commonly used in the art, and is not limited herein.
Wherein R is the following group:
Figure BDA0003429899590000032
further, the PG protecting group is specifically any one of Boc (t-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Fmoc (fluorenylmethoxycarbonylcarbonyl chloride), Bn (benzyl), PMB (p-methoxybenzyl), Me (methyl), Tfa (trifluoroacetyl), Ac (acetyl). The specific structural formula is as follows:
Figure BDA0003429899590000041
based on the difference between the PG protecting substituent and the R substituent, the compounds II obtained by the above method are (hereinafter, merely illustrated, and not meant to limit the scope of the present invention):
typical compounds include:
N-Boc- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester
Figure BDA0003429899590000042
N-Boc- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid benzyl ester
Figure BDA0003429899590000051
N-Boc- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid ethyl ester
Figure BDA0003429899590000052
N-Cbz- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester
Figure BDA0003429899590000053
N-Cbz- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid ethyl ester
Figure BDA0003429899590000054
N-Cbz- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
Figure BDA0003429899590000055
N-Fmoc- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
Figure BDA0003429899590000056
N-Bn- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester
Figure BDA0003429899590000061
N-Bn- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid ethyl ester
Figure BDA0003429899590000062
N-Bn- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
Figure BDA0003429899590000063
N-Ac- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester
Figure BDA0003429899590000064
N-Ac- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
Figure BDA0003429899590000065
N-PMB- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester
Figure BDA0003429899590000066
N-Tfa- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
Figure BDA0003429899590000067
Further, the 2, 2-dihalogenated propane is one or more of 2, 2-dibromopropane, 2, 2-dichloropropane, 2, 2-diiodopropane and gem-dihalogenated isopropane mixed with halogens;
wherein the gem-dihalogenated isopropane of mixed halogens is:
Figure BDA0003429899590000071
that is, 2, 2-dihalopropane is 2, 2-dibromopropane, 2, 2-dichloropropane, 2, 2-diiodopropane and geminally dihaloisopropane of mixed halogens are respectively:
Figure BDA0003429899590000072
further, the carboxylic acid esters include methyl esters, ethyl esters, tert-butyl esters, benzyl esters, and the like.
The synthesis method of the N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate is a further preferable technical scheme, and specifically comprises the following steps:
adding an organic solvent I, a zinc reagent, 2, 2-dihalogenated propane and a compound I into a reaction container, replacing with nitrogen, stirring, controlling the temperature to be-78-120 ℃, and reacting for 3-24 hours, wherein a catalyst is required to be added in the reaction, the adding time of the catalyst can be added together with the organic solvent I, the zinc reagent, the 2, 2-dihalogenated propane and the compound I, or the catalyst can be added after the target temperature is reached (-78-120 ℃); then removing residual zinc powder, quenching reaction, separating liquid, extracting, merging organic phases, drying and concentrating to obtain a compound II, namely the N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate;
for example: adding an organic solvent I, a zinc reagent, 2, 2-dihalogenated propane, a compound I and a catalyst into a reaction vessel, replacing with nitrogen, stirring, and reacting for 3-24 hours at the temperature of-78-120 ℃; then removing residual zinc powder, quenching reaction, separating liquid, extracting, merging organic phases, drying and concentrating to obtain a compound II, namely the N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate;
for example: adding an organic solvent I, a zinc reagent, 2, 2-dihalogenated propane and a compound I into a reaction vessel, replacing with nitrogen, stirring, controlling the temperature to be-78-120 ℃, adding a catalyst, and reacting for 3-24 hours; then removing residual zinc powder, quenching reaction, separating liquid, extracting, merging organic phases, drying and concentrating to obtain a compound II, namely the N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate;
wherein the molar ratio of the 2, 2-dihalopropane to the compound I is from 1:1 to 30: 1;
further, the molar ratio of the 2, 2-dihalopropane to the compound I is from 1:1 to 10: 1;
further, the molar ratio of the 2, 2-dihalopropane to the compound I is from 1:1 to 5: 1;
further, the molar ratio of the 2, 2-dihalopropane to the compound I is from 1:1 to 3: 1;
wherein the addition amount of the organic solvent I is 3-60 times of the volume of the compound I;
wherein the molar ratio of the zinc reagent to the compound I is 1-20: 1;
the adding amount of the catalyst is 0.1-300% of the mass of the compound I;
as a preferred technical scheme, the synthesis method comprises the following steps:
adding an organic solvent I, a zinc reagent, 2, 2-dihalogenopropane, a compound I and a catalyst into a reaction vessel, replacing with nitrogen, stirring, and reacting for 6 hours at the temperature of 65 ℃; then removing residual zinc powder, quenching reaction, separating liquid, extracting, merging organic phases, drying and concentrating to obtain a compound II, namely the N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate;
further, the organic solvent I is one or more of replaceable ether solvents such as diethyl ether, methyl tertiary ether, methyl cyclopentyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and the like or other inert solvents;
further, the other inert solvent is one or more of toluene, DMF, NMP, ethyl acetate and isopropyl acetate.
Further, the catalyst includes titanium tetrachloride, iodine, diethyl zinc, ethyl zinc iodide, methyl iodide and the like which can activate the reaction;
the zinc reagent is one or more of zinc powder, a zinc-copper compound and a zinc-silver compound;
the zinc-copper compound is a mixture of zinc powder and copper salt, or is obtained by in-situ reaction of the zinc powder and the copper salt, or is a zinc-copper compound prepared in advance; or zinc-copper alloy powder;
the copper salt is one or more of copper sulfate, copper chloride, cuprous iodide and cuprous bromide;
the zinc-silver compound is a mixture of zinc powder and silver salt, or is obtained by in-situ reaction of the zinc powder and the silver salt.
As a preferred technical scheme, the synthesis method comprises the following steps:
sequentially adding isopropyl ether, zinc powder, cuprous chloride, 2, 2-dibromopropane and a 1- (tert-butyl) 2-compound I into a reaction bottle, replacing with nitrogen, heating to 65 ℃ under stirring, and slightly refluxing; injecting a catalyst into the mixture by an injector at one time, and performing reflux reaction for 6 hours; after the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into an ammonium chloride aqueous solution, stirring until all the residual zinc powder disappears, quenching the reaction, separating the liquid, extracting the water phase twice by using ethyl acetate, combining the organic phases, drying by using anhydrous sodium sulfate, and concentrating to obtain a crude product of a compound II;
and recrystallizing the crude product by using a petroleum ether/ethyl acetate system to obtain a compound II product.
The invention also discloses a synthesis method of (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salts thereof, which is characterized by comprising the following steps:
further deprotecting the compound II prepared by the above method to obtain a compound III or a salt thereof (compound IV) which is (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and a salt thereof;
the deprotection process can be performed by the method in the prior art, and is not limited herein.
Figure BDA0003429899590000091
Or:
Figure BDA0003429899590000092
or:
Figure BDA0003429899590000093
that is to say that the position of the first electrode,
the synthetic route for compound III or a salt thereof (compound IV) is as follows:
Figure BDA0003429899590000094
or:
Figure BDA0003429899590000095
or:
Figure BDA0003429899590000101
wherein PG is a protecting group.
Wherein PG is a commonly used protecting group in the art and is not limited herein. As a further preferred variant, see the above list of PG protecting groups.
Wherein R is the following group:
Figure BDA0003429899590000102
further, the PG protecting group is specifically any one of Boc (t-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Fmoc (fluorenylmethoxycarbonylcarbonyl chloride), Bn (benzyl), PMB (p-methoxybenzyl), Me (methyl), Tfa (trifluoroacetyl), Ac (acetyl).
Further, the 2, 2-dihalogenated propane is one or more of 2, 2-dibromopropane, 2, 2-dichloropropane, 2, 2-diiodopropane and gem-dihalogenated isopropane mixed with halogens;
further, the acid group is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, oxalic acid and tartaric acid;
further, the acid group is hydrochloric acid.
The invention is characterized in that a three-membered ring key intermediate is directly constructed by using a cheap and easily obtained double bond substrate compound I and easily obtained geminal dihalogenopropane through Simmons-Smith cyclopropanation. Compared with the prior synthesis method, the method shortens the synthesis which needs about 8 steps to 3 steps, obviously reduces the synthesis cost and is more environment-friendly.
Drawings
FIG. 1 is a HNMR CDCl3400MHz spectrum of compound TM1(3- (tert-butyl) 2-methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate) of example 1;
FIG. 2 is a spectrum of the compound TM2 (methyl (1R,2S,5S) -3-acetyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate) HNMR CDCl3400MHz in example 4;
FIG. 3 is a HNMR CDCl3 spectrum of methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate hydrochloride salt of the compound of example 3;
FIGS. 4 and 5 show LCMS (ESI positive) of the compound TM2 (methyl (1R,2S,5S) -3-acetyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate) of example 4;
FIGS. 6 and 7 show LCMS (ESI positive) analysis of the compound TM1(3- (tert-butyl) 2-methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate) of example 1.
Detailed Description
The present invention is further illustrated by the following specific examples, it should be noted that, for those skilled in the art, variations and modifications can be made without departing from the principle of the present invention, and these should also be construed as falling within the scope of the present invention.
A method of synthesizing an N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate ester, the method comprising:
the synthesis method comprises the following steps of carrying out Simmons-Smith cyclopropanation reaction on a compound I (the structural formula of the compound I is shown in the specification) and 2, 2-dihalopropane to obtain a compound II, namely a synthetic method of N-protected methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic ester;
in some embodiments, the 2, 2-dihalopropane is one or more of 2, 2-dibromopropane, 2, 2-dichloropropane, 2, 2-diiodopropane, and geminally dihaloisopropanes of mixed halogens; the method comprises the following specific steps:
Figure BDA0003429899590000111
in some embodiments, the carboxylic acid esters include methyl esters, ethyl esters, t-butyl esters, benzyl esters, and the like.
In some embodiments, compound I is prepared by a prior art method, and compound I can be prepared from a wide-source and inexpensive starting material. Are not described in detail herein, nor are they intended to be limiting.
The synthetic route is as follows:
Figure BDA0003429899590000121
wherein PG is a protecting group, PG is a protecting group commonly used in the art, and is not limited herein, and in some embodiments, the PG protecting group is specifically any one of Boc (t-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Fmoc (fluorenylmethoxycarbonylcarbonyl chloride), Bn (benzyl), PMB (p-methoxybenzyl), Me (methyl), Tfa (trifluoroacetyl), Ac (acetyl).
Wherein R is the following group:
Figure BDA0003429899590000122
based on the difference between the PG protecting substituent and the R substituent, the compounds II obtained by the above method are (hereinafter, merely illustrated, and not meant to limit the scope of the present invention):
compounds II prepared in some embodiments include:
N-Boc- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester
The compound I is
Figure BDA0003429899590000131
When the product compound II is obtained
Figure BDA0003429899590000132
N-Boc- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-Carboxylic acid benzyl ester
The compound I is
Figure BDA0003429899590000133
When the product compound II is obtained
Figure BDA0003429899590000134
N-Boc- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid ethyl ester
The compound I is
Figure BDA0003429899590000135
When the product compound II is obtained
Figure BDA0003429899590000136
N-Cbz- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid methyl ester
The compound I is
Figure BDA0003429899590000137
When the product compound II is obtained
Figure BDA0003429899590000138
N-Cbz- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid ethyl ester
The compound I is
Figure BDA0003429899590000139
When the product compound II is obtained
Figure BDA00034298995900001310
N-Cbz- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester
The compound I is
Figure BDA00034298995900001311
When the product compound II is obtained
Figure BDA00034298995900001312
N-Fmoc- (1R,2S,5S) -6, 6-dimethyl-3-Azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester
The compound I is
Figure BDA0003429899590000141
When the product compound II is obtained
Figure BDA0003429899590000142
N-Bn- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid methyl ester
The compound I is
Figure BDA0003429899590000143
When the product compound II is obtained
Figure BDA0003429899590000144
N-Bn- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid ethyl ester
The compound I is
Figure BDA0003429899590000145
When the product compound II is obtained
Figure BDA0003429899590000146
N-Bn- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester
The compound I is
Figure BDA0003429899590000147
When the product compound II is obtained
Figure BDA0003429899590000148
N-Ac- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid methyl ester
The compound I is
Figure BDA0003429899590000149
When the product compound II is obtained
Figure BDA00034298995900001410
N-Ac- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester
The compound I is
Figure BDA00034298995900001411
When the product compound II is obtained
Figure BDA00034298995900001412
N-PMB- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid methyl ester
The compound I is
Figure BDA0003429899590000151
When the product compound II is obtained
Figure BDA0003429899590000152
N-Tfa- (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-carboxylic acid tert-butyl ester
The compound I is
Figure BDA0003429899590000153
When the product compound II is obtained
Figure BDA0003429899590000154
The synthesis method of the N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate in some embodiments is a further preferable technical scheme, and specifically comprises the following steps:
adding an organic solvent I, a zinc reagent, 2, 2-dihalogenopropane and a compound I into a reaction container, replacing with nitrogen, stirring, controlling the temperature to be-78-120 ℃, and reacting for 3-24 hours, wherein a catalyst is required to be added in the reaction, the adding time of the catalyst can be added together with the organic solvent I, the zinc reagent, the 2, 2-dihalogenopropane and the compound I, and the catalyst can also be added after the target temperature is reached (-78-120 ℃); then removing residual zinc powder, quenching reaction, separating liquid, extracting, merging organic phases, drying and concentrating to obtain a compound II, namely the N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate;
in some embodiments, the reaction is:
adding an organic solvent I, a zinc reagent, 2, 2-dihalogenated propane, a compound I and a catalyst into a reaction vessel, replacing with nitrogen, stirring, and reacting for 3-24 hours at the temperature of-78-120 ℃; then removing residual zinc powder, quenching reaction, separating, extracting, merging organic phases, drying and concentrating to obtain a compound II, namely N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic ester;
in other embodiments, the reaction is:
adding an organic solvent I, a zinc reagent, 2, 2-dihalogenated propane and a compound I into a reaction vessel, replacing with nitrogen, stirring, controlling the temperature to be-78-120 ℃, adding a catalyst, and reacting for 3-24 hours; then removing residual zinc powder, quenching reaction, separating liquid, extracting, merging organic phases, drying and concentrating to obtain a compound II, namely the N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate;
the amount added for each substance;
in some embodiments, the molar ratio of 2, 2-dihalopropane to compound I is from 1:1 to 30: 1;
as a preferred example, the molar ratio of 2, 2-dihalopropane to compound I is from 1:1 to 10: 1;
as a preferred example, the molar ratio of 2, 2-dihalopropane to compound I is from 1:1 to 5: 1;
as a preferred example, the molar ratio of 2, 2-dihalopropane to compound I is from 1:1 to 3: 1;
in some embodiments, the amount of the first organic solvent added is 3 to 60 times the volume of the compound I;
in some embodiments, the molar ratio of zinc reagent to compound I is 1 to 20: 1;
in some embodiments, the amount of catalyst added is 0.1% to 300% by mass of compound I.
In some embodiments, the organic solvent one is one or more of diethyl ether, methyl tert-ether, methyl cyclopentyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and other alternative ether solvents or other inert solvents;
in some embodiments, the other inert solvent is one or more of toluene, DMF, NMP, ethyl acetate, isopropyl acetate.
In some embodiments, the catalyst comprises titanium tetrachloride, iodine, diethyl zinc, ethyl zinc iodide, methyl iodide, and the like compounds that can activate the reaction;
the zinc reagent is one or more of zinc powder, a zinc-copper compound and a zinc-silver compound;
the zinc-copper compound is a mixture of zinc powder and copper salt, or is obtained by in-situ reaction of the zinc powder and the copper salt, or is a zinc-copper compound prepared in advance; or zinc-copper alloy powder;
the copper salt is one or more of copper sulfate, copper chloride, cuprous iodide and cuprous bromide;
the zinc-silver compound is a mixture of zinc powder and silver salt, or is obtained by in-situ reaction of the zinc powder and the silver salt.
As a preferred technical solution, in other embodiments, the synthesis method is:
adding an organic solvent I, a zinc reagent, 2, 2-dihalogenated propane and a compound I into a reaction container, replacing with nitrogen, stirring, controlling the temperature at 65 ℃, and reacting for 6 hours, wherein a catalyst is required to be added in the reaction, the adding time of the catalyst can be added together with the organic solvent I, the zinc reagent, the 2, 2-dihalogenated propane and the compound I, or the catalyst can be added after the target temperature (65 ℃) is reached; then cooling to room temperature, then removing residual zinc powder, quenching reaction, separating liquid, extracting, merging organic phases, drying and concentrating to obtain a compound II, namely the N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate;
as a preferred technical scheme, the synthesis method comprises the following steps:
sequentially adding isopropyl ether, zinc powder, cuprous chloride, 2, 2-dibromopropane and a 1- (tert-butyl) 2-compound I into a reaction bottle, replacing with nitrogen, and heating to 65 ℃ under stirring; injecting a catalyst into the mixture by an injector at one time, and reacting for 6 hours; after the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into an ammonium chloride aqueous solution, stirring until all the residual zinc powder disappears, quenching the reaction, separating the liquid, extracting the water phase twice by using ethyl acetate, combining the organic phases, drying by using anhydrous sodium sulfate, and concentrating to obtain a crude product of a compound II;
and recrystallizing the crude product by using a petroleum ether/ethyl acetate system to obtain a compound II product.
In some embodiments, a method of synthesizing (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salts thereof is also disclosed, as follows:
further deprotecting the compound II prepared by the above method to obtain a compound III or a salt thereof (compound IV) which is (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and a salt thereof; in these examples, the PG protecting group, R group, and 2, 2-dihalopropane are selected as above and will not be described in detail herein.
Further, the acid group is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, oxalic acid and tartaric acid
Further, the acid group is hydrochloric acid.
Figure BDA0003429899590000171
Or:
Figure BDA0003429899590000172
or:
Figure BDA0003429899590000173
that is to say that the position of the first electrode,
the synthetic route for compound III or a salt thereof (compound IV) is as follows:
Figure BDA0003429899590000174
or:
Figure BDA0003429899590000181
or:
Figure BDA0003429899590000182
the invention is illustrated below by means of specific examples:
example 1:
the preparation of the compound II is carried out,
3- (tert-butyl) 2-methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate.
Figure BDA0003429899590000183
Isopropyl ether (300mL), zinc powder (115g, 1.76mol, 4eq), cuprous chloride (174g, 1.76mol, 4eq), 2, 2-dibromopropane (266g, 1.32mol, 3eq), 1- (tert-butyl) 2-methyl (S) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylate (SM1) (100g, 0.44mol, 1eq) were added to a reaction flask in this order and replaced with nitrogen. The temperature was raised to 65 ℃ with stirring and the reflux was weak. Titanium tetrachloride (1.6g, 8.8mmol, 0.02eq) was injected into the flask in one shot with a syringe and reacted for 6 hours under reflux. After the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into 1000mL of ammonium chloride aqueous solution, stirring until all the residual zinc powder disappears, and quenching the reaction. The solution was separated, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give crude TM 1. The crude product was recrystallized from petroleum ether/ethyl acetate system to give 92.3g of TM1 product in 78% yield.
Example 2
The preparation of the compound II is carried out,
3- (tert-butyl) 2-methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 3-dicarboxylate.
Figure BDA0003429899590000191
Tetrahydrofuran (500mL), zinc powder (115g, 1.76mol, 4eq), cuprous chloride (174g, 1.76mol, 4eq), 2, 2-diiodopropane (290g, 1.32mol, 3eq), 1- (tert-butyl) 2-methyl (S) -2, 5-dihydro-1H-pyrrole-1, 2-dicarboxylate (SM1) (100g, 0.44mol, 1eq) were sequentially added to a reaction flask and replaced with nitrogen. The temperature was raised to 65 ℃ with stirring and the reflux was weak. Titanium tetrachloride (1.6g, 8.8mmol, 0.02eq) was injected into the flask in one shot with a syringe and reacted for 6 hours under reflux. After the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into 1000mL of ammonium chloride aqueous solution, stirring until all the residual zinc powder disappears, and quenching the reaction. Extracting twice with 400mL each time by adding ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, and concentrating to obtain crude TM 1. The crude product was recrystallized from petroleum ether/ethyl acetate system to give 88.9g of TM1 product in 75% yield.
Example 3
Preparation of Compound IV
Methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate hydrochloride salt:
Figure BDA0003429899590000192
the compound TM1(50 g, 0.185mol) prepared in example 1 or 2 was added to a hydrogen chloride isopropanol solution (20%, 300mL), the temperature was raised to 40 to 50 ℃ to react for 2 hours, excess solvent was evaporated under reduced pressure, 500mL of isopropyl acetate was added, and the mixture was stirred, crystallized and filtered to obtain 37g of the target methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate hydrochloride with a yield of 97%.
Example 4
The preparation of the compound II is carried out,
methyl (1R,2S,5S) -3-acetyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate:
Figure BDA0003429899590000193
anhydrous isopropyl ether (1500mL), methyl (S) -1-acetyl-2, 5-dihydro-1H-pyrrole-2-carboxylate (SM2) (100g, 0.52mol), zinc powder (309g, 4.73mol), anhydrous copper sulfate (75.5g, 0.47mol), and iodine (4.5g, 17.73mol) were added sequentially to a reaction flask, the temperature was raised to weak reflux, and 2, 2-dibromopropane (358g, 1.77mol) was added dropwise over about 1 hour. The reaction was maintained at reflux for 8 hours. After the reaction, the reaction mixture was poured into 1000ml of an aqueous ammonium chloride solution, stirred until all the zinc powder disappeared, separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give TM 292 g as an oil with a yield of 73%.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Variations or modifications in other variations may occur to those skilled in the art based upon the foregoing description. Not all embodiments need be illustrated or described herein. And obvious variations or modifications of this embodiment may be made without departing from the spirit or scope of the invention.

Claims (10)

1. A method for synthesizing N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate, which is characterized by comprising the following steps:
the compound I and 2, 2-dihalogenated propane are subjected to Simmons-Smith cyclopropanation reaction to obtain a compound II, namely a synthetic method of N-protected methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic ester;
the synthetic route is as follows:
Figure FDA0003429899580000011
wherein PG is a protecting group;
wherein R is the following group:
R：
Figure FDA0003429899580000012
2. the method of synthesizing an N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate according to claim 1,
the PG protective group is specifically any one of Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Fmoc (fluorenylmethoxycarbonyl chloride), Bn (benzyl), PMB (p-methoxybenzyl), Me (methyl), Tfa (trifluoroacetyl) and Ac (acetyl); the method comprises the following specific steps:
PG：
Figure FDA0003429899580000021
3. the method of synthesizing an N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate according to claim 1, wherein the 2, 2-dihalopropane is one or more of 2, 2-dibromopropane, 2, 2-dichloropropane, 2, 2-diiodopropane, and gem-dihaloisopropane with mixed halogens;
wherein the gem-dihalogenated isopropane of mixed halogens is:
Figure FDA0003429899580000022
that is, the 2, 2-dihalogenated propane is 2, 2-dibromopropane, 2, 2-dichloropropane, 2, 2-diiodopropane and geminally dihalogenated isopropane of mixed halogens are respectively:
Figure FDA0003429899580000023
further, the carboxylic acid esters include methyl esters, ethyl esters, tert-butyl esters, benzyl esters, and the like.
4. The method of synthesizing an N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate as claimed in claim 1 comprising the steps of:
adding an organic solvent I, a zinc reagent, 2, 2-dihalogenated propane and a compound I into a reaction container, replacing with nitrogen, stirring, controlling the temperature to be-78-120 ℃, and reacting for 3-24 hours, wherein a catalyst is required to be added in the reaction, the adding time of the catalyst can be added together with the organic solvent I, the zinc reagent, 2, 2-dihalogenated propane and the compound I, or the catalyst can be added after the target temperature is reached; then removing residual zinc powder, quenching reaction, separating liquid, extracting, merging organic phases, drying and concentrating to obtain a compound II, namely the N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate;
wherein the molar ratio of the 2, 2-dihalopropane to the compound I is from 1:1 to 30: 1;
further, the molar ratio of the 2, 2-dihalopropane to the compound I is from 1:1 to 10: 1;
further, the molar ratio of the 2, 2-dihalopropane to the compound I is from 1:1 to 5: 1;
further, the molar ratio of the 2, 2-dihalopropane to the compound I is from 1:1 to 3: 1;
wherein the addition amount of the organic solvent I is 3-60 times of the volume of the compound I;
wherein the molar ratio of the zinc reagent to the compound I is 1-20: 1;
the addition amount of the catalyst is 0.1-300% of the mass of the compound I.
5. The method for synthesizing N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate according to claim 4, wherein the organic solvent is one or more of diethyl ether, methyl tert-ether, methyl cyclopentyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methyl tetrahydrofuran, ethylene glycol dimethyl ether and other replaceable ether solvents or other inert solvents;
further, the other inert solvent is one or more of toluene, DMF, NMP, ethyl acetate and isopropyl acetate.
6. The method of synthesizing an N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate according to claim 4,
the catalyst comprises titanium tetrachloride, iodine, diethyl zinc, ethyl zinc iodide, methyl iodide and other compounds capable of activating reaction;
the zinc reagent is one or more of zinc powder, a zinc-copper compound and a zinc-silver compound;
the zinc-copper compound is a mixture of zinc powder and copper salt, or is obtained by in-situ reaction of the zinc powder and the copper salt, or is a zinc-copper compound prepared in advance; or zinc-copper alloy powder;
the copper salt is one or more of copper sulfate, copper chloride, cuprous iodide and cuprous bromide;
the zinc-silver compound is a mixture of zinc powder and silver salt, or is obtained by in-situ reaction of the zinc powder and the silver salt.
7. The method of synthesizing an N-protected (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate as claimed in claim 4 comprising the steps of: sequentially adding isopropyl ether, zinc powder, cuprous chloride, 2, 2-dibromopropane and a 1- (tert-butyl) 2-compound I into a reaction bottle, replacing with nitrogen, heating to 65 ℃ under stirring, adding a catalyst by using an injector at one time, and reacting for 6 hours; after the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into an ammonium chloride aqueous solution, stirring until all the residual zinc powder disappears, quenching the reaction, separating the liquid, extracting the water phase twice by using ethyl acetate, combining the organic phases, drying by using anhydrous sodium sulfate, and concentrating to obtain a crude product of a compound II;
and recrystallizing the crude product by using a petroleum ether/ethyl acetate system to obtain a compound II product.
8. A method for synthesizing (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salts thereof, characterized in that the method comprises the following steps:
further deprotecting compound II prepared by the process of any of claims 1-7 to give compound III or a salt thereof (compound IV) in the form of (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salts thereof;
Figure FDA0003429899580000041
or:
Figure FDA0003429899580000042
or:
Figure FDA0003429899580000043
wherein PG is a protecting group;
wherein R is the following group:
R：
Figure FDA0003429899580000051
9. the process for the synthesis of (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salts thereof according to claim 8,
the PG protective group is specifically any one of Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Fmoc (fluorenylmethoxycarbonyl chloride), Bn (benzyl), PMB (p-methoxybenzyl), Me (methyl), Tfa (trifluoroacetyl) and Ac (acetyl).
10. The process for the synthesis of (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate and salts thereof according to claim 8,
the 2, 2-dihalogenated propane is one or more of 2, 2-dibromopropane, 2, 2-dichloropropane, 2, 2-diiodopropane and gem-dihalogenated isopropane of mixed halogens;
the 2, 2-dihalogenated propane is one or more of 2, 2-dibromopropane, 2, 2-dichloropropane and 2, 2-diiodopropane;
further, the acid group is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, oxalic acid and tartaric acid;
further, the acid group is hydrochloric acid.
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